Project Summary The social environment has a clear and profound impact on human health and well being. Chronic social stress and reduced access to social support are strongly linked to major diseases of aging; as a result, social adversity is highly predictive of life expectancy itself. Recent evidence suggests that, while some of this relationship is explained by correlated factors such as smoking, obesity, and health care access, social stressors also have a direct impact on physiological function. Indeed, work in animal models has clearly demonstrated that the experience of social subordination alone can alter the function of the immune system, in part by altering gene regulation in immune cells. The goal of the proposed research is to address a key outstanding question that arises from these findings: when, and for whom, are chronic social stress effects on immune function most important? To do so, it will take advantage of dominance rank in female rhesus macaques as a model for chronic social stressor exposure in humans. Rhesus macaque females are excellent models for human social stress because they naturally organize into dominance rank hierarchies in which low ranking individuals experience increased rates of harassment, reduced social affiliation, and physiological markers of rank-related stress. Importantly, dominance rank assignments, and thus an individual's exposure to social stressors, can be manipulated in this species by manipulating group membership. Such manipulations yield a powerful experimental model for investigating the consequences of socially induced stress?an approach that is directly translatable to humans, but that is practically and ethically impossible in humans themselves. The proposed study will take advantage of this model to investigate how differential exposure to dominance rank-induced social stress causally influences gene expression in the immune system. Specifically, it will use an in vitro approach to efficiently screen for condition-specific social stress effects on gene expression levels across 30 physiologically relevant environmental conditions (e.g., pathogen exposure, steroid hormone signaling). It will complement the in vitro screen with an in vivo test of the gene regulatory and antibody response to influenza vaccination, a medical procedure in which variable responses are of particular concern as individuals age. Finally, it will test whether age, social behavior, and genotype can be used to predict interindividual variation in the strength of social stressor effects on immune regulation, and hence which individuals are most vulnerable. Together, the proposed analyses will provide much-needed insight into the factors that explain when and why individuals differ in their response to the same social stressors, as well as the potential consequences of these differences for medical treatment. The project's results will therefore have direct translational application to both identifying the most susceptible members of our aging population and suggesting tailored strategies for intervention.